Mood disorders are the second leading cause of disability worldwide. Their treatment relies predominantly on antidepressant drugs that target brain monoamines, including selective serotonin-reuptake inhibitors (SSRIs). However, even after the prolonged treatment, the antidepressant effects vary considerably, with only a small faction of patients exhibiting significant treatment effects. Since the pathogenesis of mood disorders is complex, with different contributions of genetic risk, environmental influences, and epigenetic phenotypes in individuals with the same diagnosis, the concept of a more personalized therapy is gaining increasing momentum, especially for subjects with a history of early life stress (ELS), a prominent risk factor for mood disorders and one of the strongest predictors of poor treatment response. This exploratory proposal targets the treatment of this population of patients and aims at linking the antidepressant efficacy of SSRIs to the patient's epigenetic phenotype. A recent study from this laboratory showed that a stress-susceptible strain of mice (Balb/c) exposed to ELS exhibits an adaptive epigenetic response to ELS, namely increased acetylation of histone H4 protein in the frontal cortex, that ameliorates the severity of the adult emotional psychopathology associated with ELS exposure. Strikingly, adolescent fluoxetine treatment of ELS Balb/c mice exerted powerful antidepressant effects and further elevated levels of acetylated histone H4 protein. These findings motivated the behavioral and molecular studies on different mouse strains proposed here that test the hypothesis that the effect of fluoxetine on histone H4 acetylation is a critical determinant of antidepressant efficacy and that enhanced serotonergic signaling and reduced activity of histone deacetylases (HDACs) lead to this effect. Studies on ELS Balb/c mice with reduced HDAC activity investigate the role of increased serotonergic signaling in stimulating histone H4 acetylation by comparing the effects of adolescent treatments with antidepressant drugs that either increase serotonin (5-HT) levels in the brain (fluoxetine) or that do not alter them (tianeptine). They also examine the role of 5-HT1A and 5-HT2 receptors as well as the role of brain derived neurotrophic factor-mediated trkB-signaling in mediating this effect. Additional studies on C57Bl/6 serotonin-transporter knockout mice with elevated forebrain 5-HT levels and no response to fluoxetine investigate whether reducing HDAC activity alone is sufficient to elevate histone H4 acetylation and to rescue antidepressant treatment response. Finally, studies on two additional strains of mice with low responsiveness to fluoxetine test whether co-treatment with fluoxetine and an HDAC inhibitor enhances antidepressant effects, and whether reducing HDAC activity during adolescence or adulthood has the same effect on histone H4 acetylation and antidepressant treatment response. In all studies, the possibility that drug-induced changes in histone H4 acetylation in brain are also found in peripheral blood lymphocytes will be explored. Positive results from these studies could identify a new biomarker capable of predicting antidepressant treatment response.